DE19907701A1 - New tricyclic indolyl-substituted oxazolidinone derivatives, useful as broad spectrum antibacterial agents of low toxicity - Google Patents

Abstract

3-(Tricyclic indolyl)-5-(substituted methyl)-2-oxazolidinones (I) are new. Oxazolidinone derivatives of formula (I) and their stereoisomers and salts are new. -U-V- = -CHR3-C(=D)-, -CHR4-CH2-, -CH2-CHR5- or -C(=G)-CH2-; n = 1-3; R2 = H, halo or 1-4C alkyl; E = H or halo; R3, R4 = H; 3-6C cycloalkyl; -COR6; up to 6C acyl (optionally substituted (os) by halo, OH or 1-5C alkoxy); 1-6C alkyl or 2-6C alkenyl (both os by CN, halo, COOH, up to 5C alkoxycarbonyl, OR9 or NR10R11; and/or by 6-14C aryl, itself os by halo, 1-6C alkyl, 1-6C alkoxy or up to 6C acyl); OR12; or NR13R14; D, G = O or S; R5 = OR15 or NR16R17; R6 = H, 1-6C alkoxy or NR7R8; R7 - R17 = H, Ph or 1-5C alkyl; R1 = N3, OR18, OSO2R19 or NHR21; R18 = H, 1-6C alkyl or up to 6C acyl; R19 = 1-6C alkyl or Ph; R21 = -C(=Q)-R22 or -P(O)(OR23)(OR24); Q = O or S; R22 = 1-8C alkyl, 1-8C alkoxy or CF3; 3-6C cycloalkyl (os by halo or 6-10C aryl); 6-10C aryl or 5- or 6-membered saturated or aromatic heterocycle containing 1-3 of S, N and/or O as heteroatoms (both os by 1 or 2 of halo, CN, NO2, OH and Ph); or NR25R26; R25, R26 = H, Ph, pyridyl or 1-5C alkyl (os by morpholino); R23, R24 = H or 1-4C alkyl. An Independent claim is included for the preparation of (I).

Description

The present invention relates to new oxa substituted with tricyclic indoles zolidinones, process for their preparation and their use as medicines, especially as antibacterial drugs.

From the publications US 5 254 577, US 4 705 799, EP 311 090, EP 312 000 and C.H. Park et al., J. Med. Chem. 35, 1156 (1992) are N-aryloxazolidinones with anti bacterial effect known. In addition, 3- (nitrogen-substituted) phenyl-5- beta-amidomethyloxazolidin-2-one known from EP 609 905 A1.

Furthermore, in EP 609 441 and EP 657 440 oxazolidinone derivatives with a Monoamine oxidase inhibitory effect and in EP 645 376 with effect as Adhesion receptor antagonists published.

The present invention relates to novel tricyclic indoles substituted oxazolidinones of the general formula (I)

in which
A for a rest of the formulas

stands,
in which
n represents 1, 2 or 3;
R ^{2 represents} hydrogen, halogen or straight-chain or branched alkyl having up to 4 carbon atoms;
E represents hydrogen or halogen,
R ^{3 is} hydrogen, cycloalkyl having 3 to 6 carbon atoms or a radical of the formula

means
wherein
R ⁶ denotes hydrogen, straight-chain or branched alkoxy with up to 6 carbon atoms or -NR ⁷ R ⁸ ,
wherein
R ⁷ and R ^{8 are} identical or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
or
straight-chain or branched acyl with up to 6 carbon atoms means optionally substituted by halogen, hydroxy, straight-chain or branched alkoxy with up to 5 carbon atoms,
or
straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, which are optionally substituted by cyano, halogen, carboxyl, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms, OR ⁹ or by a group of the formula -NR ¹⁰ R ¹¹ ,
wherein
R ⁹ denotes hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
R ¹⁰ and R ^{11 are the} same or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms
and / or alkyl or alkenyl are optionally substituted by aryl having 6 to 14 carbon atoms, which in turn can be substituted by halogen or by straight-chain or branched alkyl, alkoxy or acyl each having up to 6 carbon atoms,
or
OR ¹² or -NR ¹³ R ¹⁴ means
wherein
R ^{12 means} hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
R ¹³ and R ^{14 are} identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
D stands for O or S,
R ^{4 has} the meaning of R ³ given above,
R ⁵ denotes -OR ¹⁵ or -NR ¹⁶ R ¹⁷ ,
wherein
R ¹⁵ denotes hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
R ¹⁶ and R ^{17 are} identical or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
G represents O or S,
R ^{1 represents} azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or NR ²⁰ R ²¹ ,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched alkyl or acyl with up to 6 carbon atoms,
R ¹⁹ denotes straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
R ²⁰ and R ^{21 are} hydrogen,
or
R ²⁰ means hydrogen,
and
R ^{21 is} a radical of the formula

means
wherein
Q represents O or S,
R ²² denotes straight-chain or branched alkyl having up to 8 carbon atoms, straight-chain or branched alkoxy having up to 8 carbon atoms or trifluoromethyl,
or
Cycloalkyl having 3 to 6 carbon atoms, which is optionally substituted by halogen or aryl having 6 to 10 carbon atoms,
or
Aryl with 6 to 10 carbon atoms or a 5- to 6-membered saturated or aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means, the ring systems listed under R ²² optionally up to 2 times the same or different by halogen , Cyano, nitro, hydroxy or phenyl are substituted,
or
straight-chain or branched alkyl with up to 6 carbon atoms means optionally by phenoxy, benzyloxy, carboxyl, halogen or straight-chain or branched alkoxycarbonyl or acyl each having up to 6 carbon atoms or by a 5- to 6-membered heterocycle from the series S, N and / or O is substituted,
or
represents a radical of the formula -NR ²⁵ R ²⁶ ,
wherein
R ²⁵ and R ^{26 are} identical or different and denote hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by morpholine which is bonded via N,
R ²³ and R ^{24 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and their stereoisomers and salts.

According to the invention, preference is given to compounds of the general formula (I), where
A for a rest of the formulas

stands,
in which
n represents 1 or 2;
R ^{2 represents} hydrogen, F, Cl, Br, I or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl;
E represents hydrogen or F, Cl, Br, I,
R ^{3 is} hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a radical of the formula

means
wherein
R ⁶ hydrogen, methoxy, ethoxy, propoxy, isopropoxy 1-butoxy, 2-butoxy, t-butoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 1- (2-methyl) -butoxy, 1- (3- Methyl) -butoxy, 2- (3-methyl) -butoxy, 2- (2-methyl) -butoxy, or -NR ⁷ R ⁸ ,
wherein
R ⁷ and R ^{8 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,
or
Is methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, which is optionally substituted by F, Cl, Br, I, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, 1-butoxy, 2-butoxy, t-butoxy,
or
Means methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, which may be replaced by cyano, F, Cl, Br, I, carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, OR ⁹ or are substituted by a group of the formula -NR ¹⁰ R ¹¹ ,
wherein
R ⁹ denotes hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
R ¹⁰ and R ^{11 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
or
OR ¹² or -NR ¹³ R ¹⁴ means
wherein
R ¹² denotes hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
R ¹³ and R ^{14 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
D stands for O or S,
R ^{4 has} the meaning of R ³ given above,
R ⁵ denotes -OR ¹⁵ or -NR ¹⁶ R ¹⁷ ,
wherein
R ¹⁵ denotes hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
R ¹⁶ and R ^{17 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
G represents O or S,
R ^{1 represents} azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or NR ²⁰ R ²¹ ,
wherein
R ¹⁸ denotes hydrogen or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl,
R ¹⁹ denotes methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl or phenyl,
R ²⁰ and R ^{21 are} hydrogen,
or
R ²⁰ means hydrogen,
and
R ^{21 is} a radical of the formula

means
wherein
Q represents O or S,
R ²² methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, iso propoxy 1-butoxy, 2-butoxy, t-butoxy, 1-pentoxy, 2- Pentoxy, 3-pentoxy, 1- (2-methyl) -butoxy, 1- (3-methyl) -butoxy, 2- (3-methyl) -butoxy, 2- (2-methyl) -butoxy, or trifluoromethyl,
or
Means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, which is optionally substituted by F, Cl, Br, I or phenyl,
or
Is phenyl or pyridyl, which are optionally substituted up to twice in the same or different manner by F, Cl, Br, I, cyano, nitro, hydroxy or phenyl,
or
Is methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, which is optionally substituted by phenoxy, benzyloxy, carboxyl or F, Cl, Br, I,
or
represents a radical of the formula -NR ²⁵ R ²⁶ ,
wherein
R ²⁵ and R ^{26 are the} same or different and what are serum, phenyl, pyridyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, which is optionally substituted by N-linked morpholine ,
R ²³ and R ^{24 are the} same or different and are methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl.

According to the invention, these preferred compounds are particularly those Compounds preferred in which n is 1.

Furthermore, of these preferred compounds are special according to the invention preferred those compounds in which n is 2.

In particular, compounds of the general formula (I) are preferred according to the invention, in which
A for a rest of the formulas

stands,
in which
R ^{2 represents} hydrogen or F, Cl, Br;
E represents hydrogen or F, Cl, Br,
R ^{3 is} hydrogen or a radical of the formula

means
wherein
R ⁶ denotes methoxy, ethoxy, propoxy, isopropoxy 1-butoxy, 2-butoxy, t-butoxy, or -NR ⁷ R ⁸ ,
wherein
R ⁷ and R ^{8 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
or
Is methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, which are optionally substituted by OR ⁹ or by a group of the formula -NR ¹⁰ R ¹¹ ,
wherein
R ⁹ denotes hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
R ¹⁰ and R ^{11 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
or
OR ¹² or -NR ¹³ R ¹⁴ means
wherein
R ¹² denotes hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
R ¹³ and R ^{14 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
D stands for O or S,
R ^{4 has} the meaning of R ³ given above,
R ^{1 represents} azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or NR ²⁰ R ²¹ ,
wherein
R ¹⁸ denotes hydrogen or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
R ¹⁹ denotes methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl or phenyl,
R ²⁰ and R ^{21 are} hydrogen,
or
R ²⁰ means hydrogen,
and
R ^{21 is} a radical of the formula

means
wherein
Q represents O or S,
R ²² denotes methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, iso propoxy, 1-butoxy, 2-butoxy, t-butoxy or trifluoromethyl.

The compounds of the invention can be in stereoisomeric forms, i.e. H. as Enantiomers or diastereomers exist. The invention relates to both Enantiomers or diastereomers or their respective mixtures. The racem Like the diastereomers, shapes can be formed in a known manner, for example by racemate resolution or chromatographic separation processes with a given if necessary, chiral column material in the stereoisomers uniform components separate.

The following schematic diagram illustrates the correspondingly marked notations for enantiomerically pure and racemic forms:

Physiologically acceptable salts of the compounds according to the invention can Salts of the substances according to the invention with mineral acids, carboxylic acids or sulfone be acids. Z are particularly preferred. B. salts with hydrochloric acid, bromine hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfone acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, Propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or Benzoic acid.

Salts with customary bases can also be mentioned, as in for example alkali metal salts (e.g. sodium or potassium salts), alkaline earth salts (e.g. Calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as diethylamine, triethylamine, ethyldiiso propylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1- Ephenamine or methylpiperidine.

For the designation of the point of attachment of the oxazolidinone skeleton to the heterocyclic radical, the following numbering shall apply in the context of this invention (shown here by way of example for compounds of the formula (I) in which n is 1):

The oxazolidinone skeleton is preferably attached in positions 2 and 3. Be the oxazolidinone skeleton is particularly preferably attached in position 2.

Cycloalkyl generally represents a cyclic hydrocarbon radical with 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, Cycloheptyl and Cyclooctyl called. Cyclopropyl, Cyclopentane and the cyclohexane ring.

Aryl generally represents an aromatic radical with 6 to 10 carbons atoms of matter. Preferred aryl radicals are phenyl and naphthyl.

In the context of the invention, acyl stands for a straight-chain or branched Acyl radical with 1 to 6 carbon atoms. A straight-chain or ver is preferred branched lower acyl radical with 1 to 4 carbon atoms. Preferred acyl radicals are Acetyl and propionyl.

In the context of the invention, alkoxy represents a straight-chain or branched Alkoxy radical with 1 to 6 carbon atoms. A straight-chain or ver is preferred branched lower alkoxy radical with 1 to 4 carbon atoms. For example called: methoxy, ethoxy, propoxy, isopropoxy, t-butoxy, n-pentoxy and n- Hexoxy.

Alkoxycarbonyl in the context of the invention represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms. A is preferred straight-chain or branched lower alkoxycarbonyl radical with 1 to 4 carbon atoms. Examples include: methoxycarbonyl, ethoxycarbonyl, propoxy carbonyl, isopropoxycarbonyl, t-butoxycarbonyl, n-pentoxycarbonyl and n-hex oxycarbonyl.  

The compounds according to the invention are characterized in that the nitrogen atom of the oxazolidinone unit is linked to a tricyclic indole radical A which corresponds to one of the following formulas:

In this case, 1, 2 or 3 can be selected, which includes compounds with the following radicals A in the present invention:

Of the residues shown above are those in which the indole moiety is attached a five or six-membered cycle is fused, d. H. the 6,7,8,9-tetrahydro pyrido [1.2a] indoles or the 6,7-dihydrofurido [1.2a] indoles, especially prefers. In particular, the 6,7,8,9-tetrahydropyrido [1.2a] indole units are as Residues A preferred, i. H. the residues in which a six-membered to the indole unit Cyclus is fused.

According to the invention, the tricyclic indole radical A can have a substituent in the 4-position E which is hydrogen or halogen, i.e. H. F, Cl, Br or I. Erfin According to the invention, E is preferably H, F, Cl or Br, particularly preferably H or F and particularly preferred for H.

Furthermore, the tricyclic indole radical A in the 5-position can have a substituent R ² , which can be hydrogen, halogen or a straight-chain or branched alkyl having up to 4 carbon atoms. R ² is preferably H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl or t-butyl. According to the invention, it is preferably R ² H, F, Cl or Br, particularly preferably H or F and particularly preferably H.

In the radicals A shown above, R ³ can be hydrogen, a cycloalkyl having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a radical of the formula

where R ^{6 is} hydrogen, straight-chain or branched alkoxy having up to 6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy-1-butoxy, 2-butoxy, t-butoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 1 - (2-Methyl) -butoxy, 1- (3-methyl) -butoxy, 2- (3-methyl) -butoxy, 2- (2-methyl) -butoxy, or -NR ⁷ R ^{8 means} where R ⁷ and R ^{8 are the} same or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl mean. Furthermore, R ³ can be a straight-chain or branched acyl having up to 6 carbon atoms such as, for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, which may be replaced by halogen such as F, Cl, Br, I, hydroxy, straight-chain or branched alkoxy having up to 5 carbon atoms, for example Methoxy, ethoxy, propoxy, isopropoxy 1-butoxy, 2-butoxy, t-butoxy, is substituted, or a straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1-butyl, Represent 2-butyl, isobutyl, t-butyl or ethynyl, optionally by cyano, halogen such as F, Cl, Br, I, carboxyl, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms such as, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl , OR ⁹ or are substituted by a group of the formula -NR ¹⁰ R ¹¹ , wherein R ^{9 is} hydrogen, phenyl or straight-chain or branched alkyl having up to z u 5 carbon atoms such as C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, and R ¹⁰ and R ^{11 are the} same or different and are hydrogen, phenyl or, straight-chain or branched alkyl having up to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl. In addition, the above alkyl or alkenyl radicals are optionally substituted by aryl having 6 to 14 carbon atoms such as phenyl, which in turn can be substituted by halogen or by straight-chain or branched alkyl, alkoxy or acyl each having up to 6 carbon atoms.

Furthermore, R ³ can be OR ¹² or -NR ¹³ R ¹⁴ , in which R ^{12 is} hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, Isobutyl, t-butyl means, and R ¹³ and R ^{14 are the} same or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl ; Mean isobutyl, t-butyl.

According to the invention, the radical R ³ is particularly preferably hydrogen or a radical of the formula

in which R ^{6 is} methoxy, ethoxy, propoxy, isopropoxy 1-butoxy, 2-butoxy, t-butoxy, or -NR ⁷ R ⁸ , in which R ⁷ and R ^{8 are} identical or different and are hydrogen, phenyl or methyl, ethyl, Propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl mean. Furthermore, according to the invention, R ^{3 is} preferably methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, which are optionally substituted by OR ⁹ or by a group of the formula -NR ¹⁰ R ¹¹ , in which R ⁹ Is hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, R ¹⁰ and R ^{11 are} identical or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1 -Butyl, 2-butyl, isobutyl, t-butyl mean.

In addition, according to the invention, R ³ can preferably be OR ¹² or -NR ¹³ R ¹⁴ , in which R ^{12 is} hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, R ¹³ and R ^{14 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl.

The radical R ⁴ is defined according to the invention in accordance with the radical R ³ .

The radical D can be O or S, O being preferred according to the invention.

The radical R ⁵ can be -OR ¹⁵ or -NR ¹⁶ R ¹⁷ , in which R ^{15 is} hydrogen, phenyl or a straight-chain or branched C _1-5 alkyl such as, for example, methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl , Isobutyl, t-butyl, and R ¹⁶ and R ^{17 are the} same or different and are hydrogen, phenyl or a straight-chain or branched C _1-5 alkyl such as methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl , Isobutyl, t-butyl mean.

The radical G can be O or S and, according to the invention, is preferably O.

According to the invention, particular preference is given to compounds of the general formula (I) with one of the following radicals A:

wherein R ² and E are each H or F, preferably H,
R ³ is hydrogen or -COR ⁶ , in which R ⁶ is methoxy, ethoxy, propoxy or -NR ⁷ R ⁸ , in which R ⁷ and R ^{8 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl or isopropyl ,
D is O, and
R ^{4 is} methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, -CONR ⁷ R ⁸ , in which R ⁷ and R ^{8 are} identical or different and are hydrogen, phenyl or methyl, ethyl, propyl or isopropyl, or CH ₂ OR ⁹ or CH ₂ NR ¹⁰ R ¹¹ is where R ^{9 is} hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, R ¹⁰ and R ^{11 are} identical or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, or OR ¹² or -NR ¹³ R ¹⁴ means where R ^{12 is} hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, and R ¹³ and R ^{14 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl.

In the compounds of the formula (I) according to the invention, the radical R ¹ can be azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or -NR ²⁰ R ²¹ , in which R ^{18 is} hydrogen or straight-chain or branched Alkyl or acyl with up to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, R ¹⁹ denotes straight-chain or branched alkyl up to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl or phenyl, R ²⁰ and R ^{21 are} hydrogen, or R ^{20 is} hydrogen, and R ^{21 is} one Rest of the formula

means
where Q is O or S. R ²² can be straight-chain or branched alkyl having up to 8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, straight-chain or branched alkoxy having up to 8 carbon atoms, for example methoxy, Ethoxy, propoxy, isopropoxy 1-butoxy, 2-butoxy, t-butoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 1- (2-methyl) -butoxy, 1- (3-methyl) -butoxy, 2 - (3-Methyl) butoxy, 2- (2-methyl) butoxy. Furthermore, R ³ can mean trifluoromethyl or cycloalkyl having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, which is optionally substituted by halogen such as F, Cl, Br, I or aryl having 6 to 10 carbon atoms such as, for example, phenyl. In addition, R ³ can be an aryl with 6 to 10 carbon atoms such as phenyl or a 5- to 6-membered saturated or aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O as for example pyridyl, the under R ²² ring systems listed are optionally up to 2 times the same or different substituted by halogen, cyano, nitro, hydroxy or phenyl. Furthermore, R ³ can be straight-chain or branched alkyl having up to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, which may be substituted by phenoxy, benzyloxy, carboxyl or halogen, such as F, Cl, Br, I or straight-chain or ver branched alkoxycarbonyl or acyl, each having up to 6 carbon atoms or by a 5- to 6-membered heterocycle from the series S, N and / or O is substituted. Finally, R ³ can be a radical of the formula -NR ²⁵ R ²⁶ , in which R ²⁵ and R ^{26 are} identical or different and are hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 5 carbon atoms, for example methyl, ethyl, propyl, Isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, mean, which is optionally substituted by morpholine bound via N.

R ²³ and R ²⁴ may be the same or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl.

According to the invention, particular preference is given to compounds of the formula (I) in which R ^{1 is} azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or -NR ²⁰ R ²¹ , in which R ^{18 is} hydrogen or methyl, Ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl and particularly preferably hydrogen, R ^{19 is} methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl or phenyl and particularly preferably methyl, R ²⁰ and R ^{21 are} hydrogen, or R ^{20 is} hydrogen, and R ^{21 is} a radical of the formula

means where Q is O or S and R ^{22 is} methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy 1-butoxy, 2-butoxy, t -Butoxy or trifluoromethyl means.

We have also found processes for preparing the compounds of the general formula (I) according to the invention, comprising
[A] the reaction of compounds of the general formula (II)

in which
D, E, R ^{2 have} the meaning given above and
L is hydrogen or a radical of the formula

means
wherein R ^{6 represents} straight-chain or branched alkoxy having up to 6 carbon atoms;
with a reducing agent to the compounds of general formula (III)

wherein
D, E, R ² and L have the meaning given above;
[B] the reaction of the compounds of the formula (III) obtained above by a reaction sequence consisting of the group consisting of

• a) Reaction with a 1-acylaminopropane-2,3-epoxide and subsequent Reaction with carbonyldumidazole, and
• b) reaction with benzyl chloroformate and subsequent reaction with a glycidyl alkylate under basic conditions,

is selected to the compounds of general formula (I)

wherein
D, E, R ² and L have the meaning given above and
M for a residue of the formula

stands,
wherein
Q stands for O, and
R ^{25 represents} a straight-chain or branched alkyl having up to 8 carbon atoms;
or represents -OH;
[C] optionally derivatizing the compounds of formula (I) obtained above by one or more of the following reactions

• i) complete removal of the radical D or conversion of D into R ⁵ under reductive conditions and optionally derivatization, where R ^{5 is} as indicated above;
• ii) conversion of the radical L into one of the radicals R ³ or R ⁴ , where R ³ and R ^{4 are} as indicated above;
• iii) conversion of the radical M into the radical R ¹ , where R ^{1 is} as indicated above; and

[D] optionally the reaction of the compounds of formula (I) with a Acid or base to their physiologically acceptable salts.  

Some of the compounds of the general formula (II) are known or can be represented by the following reaction sequence:

where R ² , E, R ⁶ and n have the meanings given above and Hal represents a halogen, preferably Cl or Br.

The corresponding indole derivatives to be used as starting compounds are either commercially available or in a simple manner known to those skilled in the art (such as for example in Houben-Weyl, Methods of Organic Chemistry, Volume E6b1, p. 546 ff., And E6b2, p. 849 ff., Georg Thieme-Verlag, Stuttgart, 1994). accessible.

The indole derivatives to be used as starting compounds are in an inert solvent such as absolute dimethylformamide (DMF) under normal conditions with a slight (about 1.1 to 1.3 times) excess of a base such as sodium hydride and then with an about 1.1 to 1 , 5-fold excess of an ω-halocarboxylic acid ester. A 3-halogenopropanoic acid ester is used to add a five-membered ring to the indole unit. To add a six-membered ring to the indole unit, a 4-halobutanoic acid ester is used. A 5-halopentanoic acid ester is used to add a seven-membered ring to the indole unit. In the case of the above halogen carboxylic acid esters, F, Cl, Br or I, preferably Cl or Br, can serve as the halogen radical, while the alcoholic fraction, ie the radical R ⁶ , is as indicated above.

The N-substituted indole derivatives obtainable in this way are corresponding to a Dieckmann condensation by adding a base, for example an alkali metal alcoholate such as potassium t-butoxide, in excess (about 1.5 times) below normal conditions in a solvent such as tetrahydrofuran (THF) to the ge wanted tricyclic indole derivatives implemented.

Then, if desired, the ester group can be dissolved in a solvent such as an alcohol, for example ethanol, by decarboxylation under acidic loading conditions, for example by adding a mineral acid such as hydrochloric acid, and he elevated temperatures, for example heating to 50-100 ° C, preferably 60-80 ° C, be removed.

The reduction of the compounds of the formula (II) to the compounds of the formula (III) can be reduced by conventional methods of reduction known to those skilled in the art a nitro to an amino group. As examples are the Ver Use of metals such as Zn, Fe or Sn in an acidic medium, the catalytic Hydrogenation, for example using hydrogen or hydrazine Catalysts such as Raney nickel, palladium, palladium on animal charcoal or platinum, or the use of hydrides or boranes in inert solvents otherwise in the presence of a catalyst. Is preferred according to the invention the catalytic hydrogenation, especially the use of a clearly over shot (2- to 5-fold) combination of hydrazine and Raney nickel.

The compounds of formula (III) thus obtained are built up with oxazoli implemented dinonrings to the compounds of formula (I). According to the invention this implementation is done in two ways.  

The first way is to react the compounds of formula (III) with a 1-acylaminopropane epoxide and then react with a carbonic acid derivative:

where D, E, L, M, R ² and the meaning given above and R 'and R "are identical or different and for halogen such as Cl or Br, imidazole, or for an alkoxy radical having up to 4 carbon atoms such as methoxy or ethoxy or an aryloxy radical having up to 10 carbon atoms, such as phenyl or benzyl, which may optionally be substituted by one or more halogen atoms, According to the invention, preference is given to the use of phosgene, di- or triphosgene or dicarbonylimidazole, in particular dicarbonylimidazole.

The reaction of the compounds of formula (III) with an equimolar or easy increased amount of the corresponding epoxides is preferably in a halogen hydrocarbon as solvent, for example trichloromethane (Chloroform) under normal conditions, optionally with the removal of the Reaction water is carried out, the water being added for example by adding a dehydrating agent such as a molecular sieve,  Silica gel, or an alkali or alkaline earth metal sulfate such as sodium or Magnesium sulfate can be removed.

As 1-acylaminopropane-2,3-epoxides, preference is given to those in which the acyl component -COR ^{25 has} an R ²⁵ radical which stands for straight-chain or branched alkyl having up to 8 carbon atoms. R ²⁵ is preferably methyl, ethyl, propyl or isopropyl, more preferably methyl or ethyl and particularly preferably methyl. These 1-acylaminopropane-2,3-epoxides are either commercially available or in a simple manner known to those skilled in the art, for example from 3-amino-1-propene by acylation with a carboxylic acid derivative such as a carboxylic acid halide and subsequent epoxidation with, for example, a peracid such as m-Chloroperbenzoic acid accessible.

If compounds of formula (I) with a desired absolute configuration want to produce tion on the oxazolidinone ring, the first route is preferred from a chiral 1-acylaminopropane-2,3-epoxide, which also either commercially available or analogous to the synthetic route described above using asymmetric epoxidation such as one Sharpless epoxidation is accessible.

In the second step, the compounds obtained in this way are equimolar or slightly higher amount of the carbonic acid derivatives described above Structure of the oxazolidinone ring implemented. This reaction can under normal conditions conditions if necessary with heating to a temperature of 30-80 ° C, preferably point to 40-70 ° C, in a solvent such as an ether, preferably Di ethyl ether or tetrahydrofuran (THF), especially tetrahydrofuran become.

The second way to prepare the compounds of formula (I) consists of reacting the compounds of formula (III) with a slight (about 1.1 to 1.5 times) excess of benzyl chloroformate in the presence of a base and a subsequent reaction of the like Urethanes obtained with a glycidyl alkylate in a basic medium:

wherein D, E, L, M, n and R ^{2 are} as indicated above.

The first step, d. H. the reaction with ethyl chloroformate takes place in an ether, preferably diethyl ether or THF, in particular THF, as a solution medium. Sodium hydro are generally suitable as bases in this step gene carbonate, sodium methoxide, hydrazine hydrate, potassium carbonate or cesium carbonate. Sodium bicarbonate is preferred. The base comes in a lot from 1 mol to 10 mol, preferably from 1 mol to 3 mol, based on 1 mol of ver bonds of the general formula (III) used. The implementation takes place in general mean in a temperature range from -30 ° C to + 30 ° C, preferably at 0 ° C.  

The second step, d. H. the cyclization to compounds of the general formula (I) is generally carried out in a hydrocarbon such as hexane as a solvent. Alkali or alkaline earths are generally suitable as bases for this step metal alcoholates such as potassium t-butoxide or lithium t-amylate, the for example by reacting the corresponding alcohol with an alkali or alkaline earth metal organic compound such as n-butyllithium available are. The base is used in an amount of 1 mol to 10 mol, preferably 1 mol to 3 mol, based on 1 mol of urethanes used. In general, here a temperature range of -78 ° C to 0 ° C, preferably at -30 ° C.

Subsequently, the corresponding glycidyl alkylate is added in equimolar or somewhat higher amounts at a temperature of -30 ° C. to 10 ° C., preferably at 0 ° C., and the mixture is stirred under normal conditions for several hours, preferably 1 to 5 hours. The preferred glycidyl alkylates are C _1-6 alkylates, more preferably C _1-4 alkylates and especially butyrate. These glycidyl alkylates are either commercially available or can be obtained in a simple manner known to the person skilled in the art by reacting glycidol with the corresponding carboxylic acids.

If one of compounds of formula (I) with a desired absolute configuration If you want to produce the ration on the oxazolidinone ring, the second way is followed preferably from a chiral glycidyl alkylate, which is also either commercially available or analogous to the synthetic route described above Use of a chiral glycidol, which is either commercially available or from 1- Propen-3-ol via an asymmetric epoxidation such as one Sharpless epoxidation is accessible, can be represented.

The compounds of formula (I) thus obtained can, if desired, still further Are subjected to derivatization reactions which occur at preferred sites in Her position procedure can be carried out.  

For example, the radical D in the tricyclic indole unit can be converted into the corresponding thio carbonyl group by conventional methods such as, for example, reaction with P ₄ S ₁₀ . Furthermore, the radical D can either be converted into the radical R ⁵ or be completely removed under reductive conditions, wherein R ^{5 is} as indicated above. Examples of suitable reducing agents for the conversion to R ⁵ are metal hydrides such as LiAlH ₄ or NaBH ₄ . The hydroxyl group thus formed can be further converted to ethers by conventional methods such as the Williamson synthesis or to the group -NR ¹⁶ R ¹⁷ , in which R ¹⁶ and R ^{17 have} the meanings given above. In the latter case, the OH group formed is preferably converted into a good leaving group, for example the corresponding tosylate, mesylate or triflate and then with a nitrogen nucleophile such as an amine or, for the preparation of the corresponding primary amine, for example a phthalimide (Gabriel synthesis) implemented. The group -NR ¹⁶ R ¹⁷ can, however, also directly from the radical D by reaction with a nitrogen-containing nucleophile, for example ammonia, an ammonium salt or an amine, in the presence of a reducing agent such as hydrogen in the presence of a catalyst, sodium borohydride, sodium cyanoborohydride or zinc Presence of an acid such as hydrochloric acid.

Zn-Hg comes as reducing agent for the complete removal of the residue D. in acidic medium (Clemmensen reduction), hydrazine in basic medium (Wolff-Kishner reduction) or catalytic hydrogenation processes. He According to the invention, catalytic hydrogenation is preferred, with ins special Raney nickel is preferred.

The radical L, which is initially -H or -COR ⁶ according to the production process according to the invention, can either be completely removed by the decarboxylation reaction described above or converted into numerous functional groups by conventional processes. Here, for example, the reaction with amines or ammonia to give the corresponding amides (R ⁶ = -NR ⁷ R ⁸ , in which the radicals R ⁷ and R ^{8 have} the meaning given above), the reduction with, for example, organometallic compounds such as organic cadmium compounds the corresponding acyl derivatives, the reduction under conditions described above for the derivatization of D to the corresponding alcohol and, if appropriate, its conversion also described above into the corresponding ethers and amines or oxidation with, for example, pyridinium dichroate to give the corresponding aldehyde. The conversion of -COR ⁶ to the corresponding alkyl, cycloalkyl or alkenyl group is preferably carried out by decarboxylation and subsequent derivatization via the enol form of the keto group D (D = O). The conversion of -COR ⁶ into the groups -OR ¹² or -NR ¹³ R ¹⁴ is also preferably carried out via the reaction sequence decarboxylation / α-derivatization of D. All of the above reactions are familiar to the person skilled in the art and can be found in any relevant textbook.

Furthermore, the residue M can also be obtained according to the above methods Compounds of formula (I) are derivatized. So the above Process obtained hydroxy compound (M = -OH, second production route) by conventional methods such as the Williamson synthesis etherified or by Um setting with carboxylic acid derivatives such as carboxylic acid halides and in particular carboxylic acid chlorides are esterified.

The hydroxy compound (M = OH) can also be reacted with an equi molar amount or a slight excess of an alkyl or phenyl sulfone acid chloride in a halogenated hydrocarbon such as dichloro, trichloro or Tetrachloromethane, preferably dichloromethane, as a solvent with cooling to a temperature in the range from -30 ° C to + 10 ° C, preferably -5 ° C to + 5 ° C, in the presence of a base such as an amine, preferably triethyl amine, are converted into the corresponding sulfonic ester compound.

The corresponding sulfonic ester compounds (M = OSO ₂ R ¹⁹ , wherein R ¹⁹ is given above) can be reacted with an equimolar amount or a slight excess of an azide, preferably sodium azide, in a solvent such as DMF and heated to a temperature in the range of 50-100 ° C, preferably 50-80 ° C, are derivatized into the corresponding azides (M = N ₃ ).

The corresponding amine compounds (M = -NR ²⁰ R ²¹ , in which R ²⁰ and R ^{21 are given} as above) can in turn be obtained from these azides by conventional reduction reactions. According to the invention, the reduction of the azide residue is preferably carried out with (CH ₃ O) ₃ P and hydrochloric acid. The reduction is generally carried out in a temperature range from -50 ° C. to the respective boiling point of the solution, preferably from -20 ° C. to + 90 ° C. As in the other reactions described above, all inert organic solvents which do not change under the reaction conditions are also suitable as solvents. These preferably include alcohols such as methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or di ethylene glycol dimethyl ether or amides such as hexamethylphosphoric triamide or dimethylformamide, or acetic acid. It is also possible to use mixtures of the solvents mentioned.

The amine compounds (M = -NR ²⁰ R ²¹ ) obtained in this way can finally be converted into amide, urethane, urea or phosphoric acid amide derivatives by standard reactions which are known to the person skilled in the art and can be found in any relevant textbook. For this, the amine compound is reacted with the corresponding carboxylic acid, carbonic acid, carbamoyl or phosphoric acid derivatives, preferably the halides thereof. An example is the representation of thio urethanes (M = CSOR ²² , in which R ^{22 is} as given above), which is derived by reacting the amine with a significant excess of a thiocarbonic acid ester derivative such as a dithiocarbonic acid O, S diester in one Common solvents such as an alcohol, preferably methanol, ethanol or propanol, especially methanol, succeed under normal conditions.

The compounds of general formula (I) according to the invention have at ge ringer toxicity a broad antibacterial spectrum, especially against gram-positive Germs and some gram-negative bacteria as well as mycobacteria, corynebacteria, Haemophilus influenzae and anaerobic germs. Allow these properties their use as chemotherapeutic agents in human and animal medicine.

The compounds of the invention are against a broad spectrum of micro organisms effective. With their help, gram-positive germs and bacteria fights microorganisms similar to mycoplasma and those caused by these Er diseases that are more frequently caused are prevented, improved and / or cured.

The compounds according to the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly good for prophylaxis and chemotherapy of local and systemic infections in human and Suitable veterinary medicine, which are caused by such pathogens.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert, pharmaceutically suitable excipients one or more contain compounds according to the invention, or which consist of one or more inventions Active ingredients according to the invention exist, and methods for producing this accessory horse riding.

The active ingredient (s) may optionally be present in one or more of the above specified carrier substances are also present in microencapsulated form.

The therapeutically active compounds should be in the pharma listed above zeutischen preparations preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95% by weight of the total mixture.  

The pharmaceutical preparations listed above can in addition to the inventions Compounds according to the invention also contain other active pharmaceutical ingredients.

In general, it has been found in both human and veterinary medicine proven advantageous, the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg body weight each 24 hours, possibly in the form of several individual doses, to achieve the ge to deliver the desired results. A single dose contains the he or she Active substances according to the invention preferably in amounts of about 1 to about 80, ins special 3 to 30 mg / kg, body weight.

The compounds of the invention can be used for the purpose of expanding the Range of effects and to achieve an increase in effectiveness, also with others Antibiotics can be combined.

The present invention will hereinafter be described by way of non-limiting example play illustrated.  

Examples

In the examples below, all quantities relate, if not otherwise stated, percentages by weight.

List of the solvent mixtures used for chromatography

I dichloromethane: methanol
II dichloromethane
III ethyl acetate

Abbreviations

Z benzyloxycarbonyl
Boc tert-butoxycarbonyl
DMF dimethylformamide
Ph phenyl
Me methyl
THF tetrahydrofuran
CDI carbonyldiimidazole
DCE dichloroethane

1. Output connections Example I 4- (2-Ethoxycarbonyl-5-nitroindol-1-yl) butanoic acid ethyl ester

4.0 g (17.1 mmol) of 5-nitro-indole-2-carboxylic acid ethyl ester are dissolved in 200 ml of abs. Dissolved DMF and slowly added 0.89 g (22 mmol) of 60% sodium hydride at room temperature. Then 3.67 g (19 mmol) of ethyl 4-bromobutane are slowly added. The mixture is then refluxed for one hour, water is added after cooling, and the solvent is removed in vacuo. The crude product is chromatographed on silica gel (mobile phase: reactor / ethyl acetate 20: 1). The product obtained is recrystallized from isopropanol.
Yield: 4.42 g (74% of theory)
Melting point: 115 ° C
R _f (CH ₂ Cl ₂ ): 0.48

Example II 2-nitro-9-oxo-6,7,8,9-tetrahydro-pyrido [1,2a] indole-8-carboxylic acid ethyl ester

15.30 g (43.9 mmol) of the compound from Example I are added in portions to Room temperature stirring suspension of 8.08 g (72 mmol) of potassium t-butoxide in  Given 230 ml of THF. It is stirred for one hour at room temperature finally mixed with 27 ml of water and 12.2 ml of 2M hydrochloric acid and concentrated.

The residue is recrystallized from methanol.
Yield: 10.64 g (80% of theory)
Melting point: 205 to 208 ° C (with decomposition)
R _f (CH ₂ Cl ₂ ): 0.45

Example III 2-nitro-9-oxo-6,7,8,9-tetrahydro-pyrido [1,2a] indole

2 g (6.62 mmol) of the compound obtained in Example II are in a mixture from 40 ml of ethanol and 40 ml of concentrated hydrochloric acid under reflux for 1.5 hours cooked. The solvents are removed in vacuo, the residue with water added, extracted with dichloromethane, dried over magnesium sulfate and a rotates.

The crude product obtained is chromatographed on silica gel (mobile phase (CH ₂ Cl ₂ )).
Yield: 1.29 g (84% of theory)
Melting point: 186 ° C
R _f (I, 20: 1): 0.64

Example IV 2-amino-9-oxo-6,7,8,9-tetrahydro-pyrido [1,2a] indole-8-carboxylic acid ethyl ester

19.36 g (0.64 mol) of the compound obtained in Example II are placed in 1.9 l of absolute THF and mixed with 6.41 g (1.28 mol) of hydrazine hydrate and 7.7 g of Raney nickel. After 10 minutes, the Raney nickel is filtered off, washed well and the filtrate is concentrated. The crude product is crystallized from iso-propanol.
Yield 11.1 g (64% of theory)
R _f (I, 10: 1): 0.53

The compound listed in Table 1 was obtained analogously.

Table 1

Example VI (2R) -3- (8-ethoxycarbonyl-9-oxo-6,7,8,9-tetrahydro-pyrido [1,2a] indole- 2-yl) amino-2-hydroxypropyl acetamide

3.77 g (13.9 mmol) of the compound obtained via Example IV are dissolved in chloroform with 1.75 g (15.2 mmol) of (2S) -2,3-epoxypropylacetamide, and 8.31 g of silica gel are added, evaporated and left to stand at room temperature for two days. The batch is placed on a silica gel column and the product is eluted (mobile phase CH ₂ Cl ₂ / MeOH 50: 1 to 10: 1). In addition to the product, 940 mg of educt are obtained back.
Yield: 2.28 g (56% of theory, based on reacted starting material)
R _f (I, 10: 1) 0.22

The compound listed in Table 2 was obtained analogously.

Table 2

Example VIII 2- (benzyloxycarbonylamino) -9-oxo-6,7,8,9-tetrahydropyrido [1,2a] in dol-8-carboxylic acid ethyl ester

500 mg (1.84 mmol) of the compound obtained in Example IV are placed in a mixture of 4 ml of water, 10 ml of THF and 4 ml of saturated sodium bicarbonate solution. 344.6 mg (2 mmol) of benzyl chloroformate are then added at 8 ° C. and the mixture is stirred at 0 ° C. for 30 minutes. The mixture is added to water / ethyl acetate. It was extracted with ethyl acetate, the combined organic phases are dried over magnesium sulfate and evaporated. The crude product is recrystallized from ethyl acetate / petroleum ether.
Yield: 406 mg (73% of theory)
Melting point: 142 to 144 ° C
R _f (I, 20: 1): 0.69

The compound listed in Table 3 was obtained analogously.

Table 3

2. Manufacturing examples example 1 (5S) -3- (8-ethoxycarbonyl-9-oxo-6,7,8,9-tetrahydropyrido [1,2a] indole-2- yl) -5-acetaminomethyl-2-oxazolidinone

300 mg (0.77 mmol) of the compound obtained in Example VI are stirred with 163 mg (1 mmol) of N, N-carbonyldiimidazole in 40 ml of THF overnight at room temperature and then under reflux for 7 hours. After adding 82 mg (0.5 mmol) CDI again, the mixture is stirred at room temperature for 6 days. The mixture is concentrated and the crude product is chromatographed on silica gel (mobile phase I, 100: 1).
Yield: 186 mg (58% of theory)
R _f (I, 10: 1) 0.4

The compound listed in Table 4 was obtained analogously.

Table 4

Example 3 (5S) -3- (8-ethoxycarbonyl-6,7,8,9-tetrahydro-pyrido [1,2a] indol-2-yl) -5 - acetaminomethyl-2-oxozolidinone

50 mg (0.121 mmol) of the compound obtained in Example 1 are dissolved in a mixture of 5 ml of ethanol and 2.5 ml of water and refluxed for 3 hours with a spatula tip of washed Raney nickel. The catalyst is filtered off and the solvents are spun in.
Yield: 47 mg (98% of theory)
Melting point: 202 ° C
R _f (I, 10: 1): 0.56

The compound listed in Table 5 was obtained as a by-product.

Table 5

Example 5 (5R) -3- (8-ethoxycarbonyl-9-oxo-6,7,8,9-tetrahydro-pyrido [1,2a] indole-2- yl) -5-hydroxymethyl-2-oxazolidinone

371 mg (4.2 mmol) of tert-amyl alcohol are dissolved in 1 ml of hexane and 0.26 ml of n-BuLi (2.5 M in hexane) is added dropwise at -30 ° C. This solution is added dropwise to the solution of 530 mg (1.3 mmol) of the compound obtained in Example VIII, which is stirred at 0 ° C., in 2 ml of dimethylacetamide and the mixture is stirred for 15 minutes. Then 235 mg (1.63 mmol) of (R) -glycidyl butyrate are added and the mixture is stirred for 3 hours while warming to room temperature. While cooling with an ice bath, 3 ml of water, 2 ml of methanol and 0.3 ml of acetic acid are added and the mixture is stirred for 30 minutes. The resulting precipitate is isolated, washed with water and dried in vacuo.
Yield: 372 mg (70% of theory)
R _f (I, 20: 1): 0.11.

The compound listed in Table 6 was obtained analogously.

Table 6

Example 7 (5R) -3- (8-ethoxycarbonyl-9-oxo-6,7,8,9-tetrahydro-pyrido [1,2a] indole-2- yl) -5- (methylsulfonyloxymethyl) -2-oxazolidinone

325 mg (0.87 mmol) of the compound obtained in Example 4 are initially introduced into 5 ml of dichloromethane at 0 ° C., and 0.18 ml (1.29 mmol) of triethylamine and 0.07 ml (0.96 mmol) of methanesulfonic acid chloride are added . The mixture is stirred at 0 ° C. for 90 minutes, the mixture is concentrated and the crude product obtained is chromatographed on silica gel (mobile phase I, 100: 1).
Yield: 450 mg (65% of theory)
R _f (I, 20: 1) 0.625

The compound listed in Table 7 was obtained analogously.

Table 7

Example 9 (5R) -3- (8-ethoxycarbonyl-9-oxo-6,7,8,9-tetrahydro-pyrido [1,2a] indole-2- yl) -5-azidomethyl-2-oxazolidinone

240 mg (0.53 mmol) of the compound obtained in Example 6 are mixed with 45 mg (0.69 mmol) sodium azide in 5 ml DMF stirred at 70 ° C for 3 hours.

The cooled batch is poured onto ice water and extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated.
Yield: 173 mg (82% of theory)
Melting point: 86 to 88 ° C (decomposition)
R _f (III): 0.5

The compound listed in Table 8 was obtained analogously.

Table 8

Example 11 (5S) -3- (8-ethoxycarbonyl-9-oxo-6,7,8,9-tetrahydro-pyrido [1,2a] indole-2- yl) -5-aminomethyl-2-oxazolidinone hydrochloride

150 mg (0.38 mmol) of the compound obtained in Example 8 is placed in 1.7 ml of dimethoxyethane, mixed with 0.1 ml of trimethyl phosphite and stirred at 100 ° C. for 2 hours. The cooled batch is mixed with 0.08 ml of 6N hydrochloric acid and refluxed for 2 hours. The resulting precipitate is isolated, washed with methyl t-butyl ether and recrystallized from methanol / methyl t-butyl ether.
Yield: 75 mg (53% of theory)
Melting point: 207 ° C (decomposition)
R _f (I, 1: 1): 0.16

The compound listed in Table 9 was obtained analogously.

Table 9

Example 13 (5S) -3- (8-ethoxycarbonyl-9-oxo-6,7,8,9-tetrahydro-pyrido [1,2a] indole-2- yl) -5- (methoxy-thiocarbonylaminomethyl) -2-oxazolidinone

65 mg (0.175 mmol) of the compound obtained in Example 10 are placed in 2 ml of methanol and 0.11 ml (0.61 mmol) of diisopropylethylamine and 43 mg (0.35 mmol) of dithiocarbonic acid O, S-dimethyl ester are added and stirred overnight at room temperature. All volatile components are removed in vacuo and the residue is chromatographed on silica gel (mobile phase I, 80: 1).
Yield: 27 mg (34% of theory)
Melting point: 110 to 112 ° C
R _f (I, 10: 1): 0.67

The compound listed in Table 10 was obtained analogously.

Table 10

Example 15 (5S) -3- (9-Amino-6,7,8,9-tetrahydropyrido [1.2a] indol-2-yl) -5-acetyl methylamino-2-oxazolidinone

100 mg (0.29 mmol) of the compound obtained in Example 2 are initially charged with 450 mg (5.9 mmol) of ammonium acetate in 5 ml of methanol. After adding 25 mg (0.39 mmol) of sodium cyanoborohydride, the mixture is stirred for six hours at room temperature. The mixture is washed with ethyl acetate and the aqueous phase is spun in. The residue is first purified by chromatography on silica gel (running medium I, 5: 1) and then by HPLC.
Yield: 16 mg (16% of theory)
R _f (I, 10: 1): 0.19

Biological studies

The MIC values were measured using the microdilution method in BH medium certainly. Each test substance was dissolved in the nutrient medium. In the microtiter plate a series of concentrations of the test substances was obtained by serial dilution created. Overnight cultures of the pathogens were used for inoculation, the previously were diluted 1: 250 in the nutrient medium. To 100 µl of the diluted, active ingredient containing nutrient solutions were given 100 µl of inoculation solution.  

The microtiter plates were incubated at 37 ° C and after about 20 hours or after 3 read up to 5 days. The MIC value (µg / ml) gives the lowest active ingredient concentration tration where no growth was discernible.

MIC values (µg / ml)

Claims (9)

1. oxazolidinones of the general formula (I)
in which
A for a rest of the formulas
stands,
in which
n represents 1, 2 or 3;
R ^{2 represents} hydrogen, halogen or straight-chain or branched alkyl having up to 4 carbon atoms;
E represents hydrogen or halogen,
R ^{3 is} hydrogen, cycloalkyl having 3 to 6 carbon atoms or a radical of the formula
means
wherein
R ⁶ denotes hydrogen, straight-chain or branched alkoxy with up to 6 carbon atoms or -NR ⁷ R ⁸ ,
wherein
R ⁷ and R ^{8 are the} same or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
or
straight-chain or branched acyl with up to 6 carbon atoms means optionally substituted by halogen, hydroxy, straight-chain or branched alkoxy with up to 5 carbon atoms,
or
straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, which are optionally substituted by cyano, halogen, carboxyl, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms, OR ⁹ or by a group of the formula -NR ¹⁰ R ¹¹ ,
wherein
R ⁹ denotes hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
R ¹⁰ and R ^{11 are the} same or different and are hydrogen, phenyl or, straight-chain or branched alkyl having up to 5 carbon atoms
and / or alkyl or alkenyl are optionally substituted by aryl having 6 to 14 carbon atoms, which in turn can be substituted by halogen or by straight-chain or branched alkyl, alkoxy or acyl each having up to 6 carbon atoms,
or
OR ¹² or -NR ¹³ R ¹⁴ means
wherein
R ¹² denotes hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
R ¹³ and R ^{14 are} identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
D stands for O or S,
R ^{4 has} the meaning of R ³ given above,
R ⁵ denotes -OR ¹⁵ or -NR ¹⁶ R ¹⁷ ,
wherein
R ¹⁵ denotes hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
R ¹⁶ and R ^{17 are} identical or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
G represents O or S,
R ^{1 represents} azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or -NR ²⁰ R ²¹ ,
wherein
R ¹⁸ denotes hydrogen or straight-chain or branched alkyl or acyl with up to 6 carbon atoms,
R ¹⁹ denotes straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
R ²⁰ and R ^{21 are} hydrogen,
or
R ²⁰ means hydrogen,
and
R ^{21 is} a radical of the formula
means
wherein
Q represents O or S,
R ²² denotes straight-chain or branched alkyl having up to 8 carbon atoms, straight-chain or branched alkoxy having up to 8 carbon atoms or trifluoromethyl,
or
Means cycloalkyl having 3 to 6 carbon atoms, which is optionally substituted by halogen or aryl having 6 to 10 carbon atoms,
or
Aryl with 6 to 10 carbon atoms or a 5- to 6-membered saturated or aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means, the ring systems listed under R ²² optionally up to 2 times the same or different by halogen , Cyano, nitro, hydroxy or phenyl are substituted,
or
straight-chain or branched alkyl with up to 6 carbon atoms means optionally by phenoxy, benzyloxy, carboxyl, halogen or straight-chain or branched alkoxycarbonyl or acyl each having up to 6 carbon atoms or by a 5- to 6-membered heterocycle from the series S, N and / or O is substituted,
or
represents a radical of the formula -NR ²⁵ R ²⁶ ,
wherein
R ²⁵ and R ^{26 are the} same or different and are hydrogen, phenyl, pyridyl or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by N-linked morpholine,
R ²³ and R ^{24 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and their stereoisomers and salts. 2. Oxazolidinones according to claim 1, characterized in that
A for a rest of the formulas
stands,
in which
n represents 1 or 2;
R ^{2 represents} hydrogen, F, Cl, Br, I or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl;
E stands for hydrogen or your F, Cl, Br, I,
R ^{3 is} hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a radical of the formula
means
wherein
R ⁶ hydrogen, methoxy, ethoxy, propoxy, isopropoxy 1-butoxy, 2-butoxy, t-butoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 1- (2-methyl) -butoxy, 1- (3- Methyl) -butoxy, 2- (3-methyl) -butoxy, 2- (2-methyl) -butoxy, or -NR ⁷ R ⁸ ,
wherein
R ⁷ and R ^{8 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,
or
Is methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, which is optionally substituted by F, Cl, Br, I, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, 1-butoxy, 2-butoxy, t-butoxy,
or
Means methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, which may be replaced by cyano, F, Cl, Br, I, carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, OR ⁹ or are substituted by a group of the formula -NR ¹⁰ R ¹¹ ,
wherein
R ⁹ denotes hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
R ¹⁰ and R ^{11 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
or
OR ¹² or -NR ¹³ R ¹⁴ means
wherein
R ¹² denotes hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
R ¹³ and R ^{14 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
D stands for O or S,
R ^{4 has} the meaning of R ³ given above,
R ⁵ denotes -OR ¹⁵ or -NR ¹⁶ R ¹⁷ ,
wherein
R ¹⁵ denotes hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
R ¹⁶ and R ^{17 are} identical or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
G represents O or S,
R ^{1 represents} azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or -NR ²⁰ R ²¹ ,
wherein
R ¹⁸ denotes hydrogen or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl,
R ¹⁹ denotes methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl or phenyl,
R ²⁰ and R ^{21 are} hydrogen,
or
R ²⁰ means hydrogen,
and
R ^{21 is} a radical of the formula
means
wherein
Q represents O or S,
R ²² methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, iso propoxy 1-butoxy, 2-butoxy, t-butoxy, 1-pentoxy, 2- Pentoxy, 3-pentoxy, 1- (2-methyl) -butoxy, 1- (3-methyl) -butoxy, 2- (3-methyl) -butoxy, 2- (2-methyl) -butoxy, or trifluoromethyl,
or
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl means, which is optionally substituted by F, Cl, Br, I or phenyl,
or
Is phenyl or pyridyl, which are optionally substituted up to twice in the same or different manner by F, Cl, Br, I, cyano, nitro, hydroxy or phenyl,
or
Is methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, which is optionally substituted by phenoxy, benzyloxy, carboxyl or F, Cl, Br, I,
or
represents a radical of the formula -NR ²⁵ R ²⁶ ,
wherein
R ²⁵ and R ^{26 are the} same or different and what are serum, phenyl, pyridyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, which is optionally substituted by N-linked morpholine ,
R ²³ and R ^{24 are the} same or different and are methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl. 3. oxazolidinones according to claim 2, characterized in that n is 1.   4. oxazolidinones according to claim 2, characterized in that
n is 2. 5. oxazolidinones according to claim 2, characterized in that,
A for a rest of the formulas
stands,
in which
R ^{2 represents} hydrogen or F, Cl, Br;
E represents hydrogen or F, Cl, Br,
R ^{3 is} hydrogen or a radical of the formula
means
wherein
R ⁶ denotes methoxy, ethoxy, propoxy, isopropoxy 1-butoxy, 2-butoxy, t-butoxy, or -NR ⁷ R ⁸ ,
wherein
R ⁷ and R ^{8 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
or
Is methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, which are optionally substituted by OR ⁹ or by a group of the formula -NR ¹⁰ R ¹¹ ,
wherein
R ⁹ denotes hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
R ¹⁰ and R ^{11 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
or
OR ¹² or -NR ¹³ R ¹⁴ means
wherein
R ¹² denotes hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
R ¹³ and R ^{14 are the} same or different and are hydrogen, phenyl or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
D stands for O or S,
R ^{4 has} the meaning of R ³ given above,
R ^{1 represents} azido or a radical of the formula -OR ¹⁸ , -O-SO ₂ -R ¹⁹ or -NR ²⁰ R ²¹ ,
wherein
R ¹⁸ denotes hydrogen or methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl,
R ¹⁹ denotes methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl or phenyl,
R ²⁰ and R ^{21 are} hydrogen,
or
R ²⁰ means hydrogen,
and
R ^{21 is} a radical of the formula
means
wherein
Q represents O or S,
R ^{22 is} methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, iso propoxy, 1-butoxy, 2-butoxy, t-butoxy or trifluoromethyl. 6. A process for the preparation of oxazolidinones of the general formula (I) comprising
[A] the reaction of compounds of the general formula (II)
in which
D, E, R ^{2 have} the meaning defined in claim 1 and
L is hydrogen or a radical of the formula
means
wherein R ^{6 represents} straight-chain or branched alkoxy having up to 6 carbon atoms;
with a reducing agent to the compounds of general formula (III)
wherein
D, E, R ² and L have the meaning given above;
[B] the reaction of the compounds of the formula (III) obtained above by a reaction sequence consisting of the group consisting of
c) reaction with a 1-acylaminopropane-2,3-epoxide and subsequent reaction with carbonyldiimidazole, and
d) reaction with benzyl chloroformate and subsequent reaction with a glycidyl alkylate under basic conditions,
is selected to the compounds of the general formula (IV)
wherein
D, E, R ² and L have the meaning given above and
M for a residue of the formula
stands,
wherein
Q stands for O, and
R ^{25 represents} a straight-chain or branched alkyl having up to 8 carbon atoms;
or represents -OH;
[C] optionally the derivatization of the compounds of formula (I) obtained above by one or more of the following reactions
iv) complete removal of the residue D or conversion of D into R ⁵ under reductive conditions and optionally derivatization, wherein R ^{5 is} as defined in claim 1;
v) converting the radical L into one of the radicals R ³ or R ⁴ , where R ³ and R ^{4 are} as defined in claim 1;
vi) conversion of the radical M into the radical R ¹ , where R ^{1 is} as defined in claim 1; and
[D] optionally the reaction of the compounds of formula (I) with an acid or base to their physiologically acceptable salts. 7. Pharmaceutical composition containing oxazolidinones of the general my formula (I) according to any one of claims 1 to 5 in combination with a pharmaceutically acceptable carrier or with pharmazeu table compatible additives. 8. oxazolidinones of the general formula (I) according to any one of claims 1 to 5 for use as a medicine.   9. Use of oxazolidinones of the general formula (I) according to one of claims 1 to 5 for the manufacture of medicaments for treatment bacterial infections.